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Title: Discovery of Selective and Noncovalent Diaminopyrimidine-Based Inhibitors of Epidermal Growth Factor Receptor Containing the T790M Resistance Mutation

Activating mutations within the epidermal growth factor receptor (EGFR) kinase domain, commonly L858R or deletions within exon 19, increase EGFR-driven cell proliferation and survival and are correlated with impressive responses to the EGFR inhibitors erlotinib and gefitinib in nonsmall cell lung cancer patients. Approximately 60% of acquired resistance to these agents is driven by a single secondary mutation within the EGFR kinase domain, specifically substitution of the gatekeeper residue threonine-790 with methionine (T790M). Due to dose-limiting toxicities associated with inhibition of wild-type EGFR (wtEGFR), we sought inhibitors of T790M-containing EGFR mutants with selectivity over wtEGFR. Here in this paper, we describe the evolution of HTS hits derived from Jak2/Tyk2 inhibitors into selective EGFR inhibitors. X-ray crystal structures revealed two distinct binding modes and enabled the design of a selective series of novel diaminopyrimidine-based inhibitors with good potency against T790M-containing mutants of EGFR, high selectivity over wtEGFR, broad kinase selectivity, and desirable physicochemical properties.
Authors:
 [1] ;  [2] ;  [1] ;  [1] ;  [1] ;  [3] ;  [1] ;  [4] ;  [4] ;  [3] ;  [4] ;  [5] ;  [1] ;  [6] ;  [7] ;  [4] ;  [7] ;  [8] ;  [1] ;  [4] more »;  [7] ;  [2] ;  [2] ;  [8] ;  [1] « less
  1. Genentech Inc., South San Francisco, CA (United States). Dept. of Discovery Chemistry
  2. Genentech Inc., South San Francisco, CA (United States). Dept. of Structural Biology
  3. Genentech Inc., South San Francisco, CA (United States). Dept. of Drug Metabolism and Pharmacokinetics
  4. Argenta, Harlow, Essex (United Kingdom). Charles River Early Discovery Facility
  5. Genentech Inc., South San Francisco, CA (United States). Dept. of Biochemical and Cellular Pharmacology
  6. Genentech Inc., South San Francisco, CA (United States). Dept. of Molecular Oncology
  7. Genentech Inc., South San Francisco, CA (United States). Dept. of Biochemical and Cellular Pharmacology
  8. Genentech Inc., South San Francisco, CA (United States). Dept. of Protein Expression
Publication Date:
OSTI Identifier:
1168859
Grant/Contract Number:
AC02-05CH11231; 085P1000817; AC02-06CH11357
Type:
Accepted Manuscript
Journal Name:
Journal of Medicinal Chemistry
Additional Journal Information:
Journal Volume: 57; Journal Issue: 23; Journal ID: ISSN 0022-2623
Publisher:
American Chemical Society (ACS)
Research Org:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22); National Institutes of Health (NIH)
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES